共查询到20条相似文献,搜索用时 833 毫秒
1.
Xiaofan Zhang Julia Li Zhong Wei Liu Zuhua Gao Xia Xue Pan Yue Limei Wang Cuirong Zhao Wenfang Xu Xianjun Qu 《Cancer chemotherapy and pharmacology》2010,66(1):11-19
Purpose
N3-o-toluyl-fluorouracil (TFU), the prodrug of 5-fluorouracil (5-FU), is the metabolite of N1-acetyl-N3-o-toluyl-fluorouracil (atofluding). In the present study, we aimed to evaluate the efficacy of TFU on the inhibition of human hepatocellular carcinoma cells via sustained release of 5-FU. The metabolism of TFU underlying the inhibitory effect was also analyzed.Methods
In vitro assays, inhibition of cell growth by TFU was evaluated by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide method. The levels of TFU and 5-FU in the cell culture supernatant fluid were measured by high-performance liquid chromatography (HPLC). In vivo assays, the efficacy of TFU was evaluated in a human hepatocellular carcinoma xenograft mice model after 3 weeks of oral administration. The distributions of TFU and 5-FU in plasma and homogenate tissues including liver, lung and tumor were determined by HPLC.Results
N3-o-toluyl-fluorouracil weakly inhibited the proliferation of SMMC-7721 and PLC/PRF/5 cells in the absence of liver microsomal enzymes. In contrast, the inhibition rates were significantly increased in the presence of these enzymes. HPLC results revealed that TFU was metabolized slowly by liver microsomal enzymes and therefore the concentration of 5-FU was gradually increased with a longer retention time in cell culture supernatant fluid. The efficacy of TFU was confirmed in SMMC-7721 xenografts in Balb/c athymic (nu+/nu+) mice model. TFU treatment induced inhibition of SMMC-7721 growth with few side effects. HPLC results showed that high levels of TFU were still in liver 48 h after the end of oral administration, implying that TFU preferentially accumulated in liver with slow conversion to 5-FU by enzymes. This led to a long-lasting concentration of 5-FU in plasma. Further, a high level of 5-FU was found in tumors with a relatively low level in lungs. These results suggest that the metabolite of TFU was preferentially converted or taken up by tumor cells. The distributions of 5-FU may contribute to its high anti-tumor activity and low adverse reactions in vivo.Conclusion
These results demonstrate that TFU is a promising prodrug of 5-FU for cancer treatment via sustained release of 5-FU in liver. 相似文献2.
Andrea Réti Éva Pap Vilmos Adleff András Jeney Judit Kralovánszky Barna Budai 《Cancer chemotherapy and pharmacology》2010,66(2):219-227
Purpose
To prove that 5-FU cytotoxicity could be increased by combination with low-dose non-steroidal anti-inflammatory drugs (NSAIDs) (indomethacin or NS-398) in high cyclooxygenase-2- (COX-2) expressing cells and xenografts through the modulation of dihydropyrimidine dehydrogenase (DPD) mRNA expression and/or enzyme activity.Methods
HT-29 cells were grown on collagen IV coated plates (HT-29-C). The antiproliferative effect of 5-fluorouracil (5-FU) ± NSAIDs was examined on non-COX-2 expressing HT-29 and COX-2-expressing HT-29-C cells by sulphorhodamine B assay. The COX-2 and DPD expressions were visualized by immunofluorescent staining, and prostaglandin E2 levels were measured by ELISA kit. The HT-29 xenograft was established in SCID mice and treated with 5-FU ± NSAIDs for 5 days. The tumor volume, enzyme activity, and DPD mRNA expression were investigated by caliper, radioenzymatic method, and real-time RT-PCR, respectively. The drug interaction was calculated for both combinations (5-FU + indomethacin and 5-FU + NS-398).Results
Collagen IV up-regulated significantly the COX-2 and DPD mRNA, and protein expressions, and also their enzyme activities in HT-29 cells. NSAIDs enhanced in a synergistic manner the cytotoxic effect of 5-FU treatment both in vitro and in vivo. Downregulation of DPD was observed after 5-FU monotherapy, but the combined effect of NSAIDs and 5-FU on DPD mRNA expression, and enzyme activity was superior to the effect of 5-FU alone.Conclusions
Since 5-FU + NSAID treatment can alter the DPD enzyme activity resulting in an enhanced cytotoxic effect, further studies in clinical practice are warranted. 相似文献3.
Allison Pledgie-Tracy Madhavi Billam Amy Hacker Michele D. Sobolewski Patrick M. Woster Zhe Zhang Robert A. Casero Nancy E. Davidson 《Cancer chemotherapy and pharmacology》2010,65(6):1067-1081
Introduction
Polyamine analogues have demonstrated significant activity against human breast cancer cell lines as single agents as well as in combination with other cytotoxic drugs. This study evaluates the ability of a polyamine analogue N 1,N 11-bis(ethyl)norspermine (BENSpm) to synergize with six standard chemotherapeutic agents, 5-fluorouracil (FU), fluorodeoxyuridine, cis-diaminechloroplatinum(II) (C-DDP), paclitaxel, docetaxel, and vinorelbine.Materials and methods
Four human breast cancer cell lines (MDA-MB-231, MCF-7, Hs578t, and T47D) and one immortalized, non-tumorigenic mammary epithelial cell line (MCF-10A) were used for in vitro combination studies with BENSpm and cytotoxic drugs. Xenograft mice models generated with MDA-MB-231 cells were used for in vivo studies with BENSpm and paclitaxel.Results and conclusion
BENSpm exhibited synergistic inhibitory effect on cell proliferation in combination with 5-FU or paclitaxel in human breast cancer cell lines (MDA-MB-231 and MCF-7) and was either antagonistic or less effective in the non-tumorigenic MCF-10A cell line. Synergism was highest with 120 h concomitant treatment or pre-treatment with BENSpm for 24 h followed by concomitant treatment for 96 additional hours. Since the cytotoxic effects of many polyamine analogues and cytotoxic agents are believed to act, in part, through induction of the polyamine catabolic enzymes SSAT and SMO, the role of these enzymes on synergistic response was evaluated in MDA-MB-231 and MCF-7 treated with BENSpm and 5-FU or paclitaxel. Combination treatments of BENSpm with 5-FU or paclitaxel resulted in induction of SSAT mRNA and activity in both cell lines compared to either drug alone, while SMO mRNA and activity were increased only in MDA-MB-231 cells. Induction was greater with BENSpm/paclitaxel combination than BENSpm/5-FU. Further, RNAi studies demonstrated that both SSAT and SMO play a significant role in the response of MDA-MB-231 cells to treatment with BENSpm and 5-FU or paclitaxel. In MCF-7 cells, only SSAT appears to be involved in the response to these treatments. In an effort to translate combination studies from in vitro to in vivo, and to form a basis for clinical setting, the in vivo therapeutic efficacy of BENSpm alone and in combination with paclitaxel on tumor regression was evaluated in xenograft mice models generated with MDA-MB-231 cells. Intraperitoneal exposure to BENSpm or taxol singly and in combination for 4 weeks resulted in significant inhibition in tumor growth. These findings help elucidate the mechanisms involved in synergistic drug response and support combinations of polyamine analogues with chemotherapeutic agents which could potentially be used in the treatment of breast cancer. 相似文献4.
5.
Hemerson Iury F. Magalh?es Daniel P. Bezerra Bruno C. Cavalcanti Diego V. Wilke Rodrigo Rotta D��nis P. de Lima Adilson Beatriz Ana Paula N. N. Alves Fl��vio da S. Bitencourt Ingrid S. T. de Figueiredo Nylane M. N. Alencar Let��cia V. Costa-Lotufo Manoel Odorico Moraes Claudia Pessoa 《Cancer chemotherapy and pharmacology》2011,68(1):45-52
Purpose
(4-Methoxyphenyl)(3,4,5-trimethoxyphenyl)methanone (PHT) is a phenstatin analog compound. PHT is a known tubulin inhibitor that has potent cytotoxic activity. In the present study, PHT was synthesized and its antitumor activity was determined using in vitro and in vivo experimental models.Methods
The in vitro cytotoxic activity of the PHT was determined by the MTT assay. The antimitotic and hemolytic effects were determined based on the inhibition of sea urchin embryo development and lysis of mouse erythrocytes, respectively. In vivo antitumor activity was assessed in mice inoculated with sarcoma 180 cells.Results
In vitro, PHT displayed cytotoxicity in tumor cell lines, showing IC50 values in the nanomolar range. In addition, it inhibited sea urchin embryo development during all phases examined, first and third cleavage and blastula stage. However, PHT did not induce hemolysis using mouse erythrocytes, suggesting that the cytotoxicity of PHT does not involve membrane damage. The in vivo study demonstrated tumor inhibition rates of 30.9 and 48.2% for PHT at doses of 20 and 40?mg/kg, respectively. In addition, PHT was also able to increase the response elicited by 5-fluorouracil (5-FU) from 33.3 to 55.7%. The histopathological analysis of liver, kidney, and spleen showed that they were just moderately affected by PHT treatment. Neither enzymatic activity of transaminases nor urea levels were significantly affected. Hematological analysis showed leukopenia after 5-FU treatment, but this effect was prevented when 5-FU was combined with PHT.Conclusions
In conclusion, PHT exhibited in vitro and in vivo antitumor effects without substantial toxicity. 相似文献6.
Purpose
5-Fluorouracil (5-FU) is used for the treatment of colorectal cancer, but has low therapeutic response rate and severe side effects. Recently, fish oil (FO) rich in n-3 polyunsaturated fatty acids has been preferred to chemosensitize tumor cells to anticancer drugs. Therefore, the current study is designed to evaluate chemotherapeutic efficacy and toxicity profile of 5-FU in combination with FO in 1,2-dimethylhydrazine dihydrochloride/dextran sulfate sodium (DMH/DSS)-induced colon cancer model.Methods
The therapeutic efficacy of 5-FU along with FO was analyzed through assessment of survival rate, tumor burden, volume, serum sialic acid levels, cytokeratin 19 (CK19) expression and index of cell proliferation such as cell cycle progression. Toxicological aspects were evaluated by standard functional and structural parameters related to spleen, gastrointestinal, liver and kidney.Results
In the present study, 5-FU in combination with FO increased the survival rate in carcinogen-treated animals. Synergism of 5-FU and FO was also reflected in significant inhibition in tumor growth and serum sialic acid levels in DMH/DSS model. Moreover, the combination dosage significantly augmented the inhibition of cell cycle progression, as shown by CK19 expression. Additionally, FO ameliorated hematologic depression, gastrointestinal, hepatic and renal toxicity caused by 5-FU as substantiated by a marked improvement in structural and functional alterations of these organs.Conclusion
The supplementation of FO is potentially a promising option for increasing the therapeutic potential and mitigating the side effects of 5-FU. 相似文献7.
Yi-kang Shi Zhong-hua Li Xi-qian Han Ji-hu Yi Zhen-hua Wang Jing-li Hou Cong-ran Feng Qing-hong Fang Hui-hui Wang Peng-fei Zhang Feng-shan Wang Jie Shen Peng Wang 《Cancer chemotherapy and pharmacology》2010,66(6):1131-1140
Purpose
The histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA) enhances taxol-induced antitumor effects against some human cancer cells. The aim of this study is to investigate whether SAHA can enhance taxol-induced cell death against human breast cancer cells and to illustrate the mechanism in detail.Methods
A panel of eight human breast cancer cell lines and an immortalized human breast epithelial cell line were used to determine the inhibitory effects of SAHA, taxol, or their combination by MTT assay. The effects of SAHA with or without taxol on cell cycle distributions, apoptosis, and protein expressions were also examined. The inhibitory effects on tumor growth were characterized in vivo in BALB/c nude mice bearing a breast cancer xenograft model.Results
Taxol-resistant and multi-resistant breast cancer cells were as sensitive to SAHA as taxol-sensitive breast cancer cells. A dose-dependent synergistic growth inhibition was found in all the tested breast cancer cell lines treated with the SAHA/taxol combinations. The synergetic effect was also observed in the in vivo xenograft tumor model. The cell cycle analysis and apoptosis assay showed that the synergistic effects resulted from enhanced G2/M arrest and apoptosis.Conclusions
SAHA increased the anti-tumor effects of taxol in breast cancer in vitro and in vivo. The combination of SAHA and taxol may have therapeutic potential in the treatment of breast cancer. 相似文献8.
Autumn J. McRee Janine M. Davies Hanna G. Sanoff Richard M. Goldberg Stephen Bernard E. Claire Dees Kimberly Keller Anastasia Ivanova Bert H. O’Neil 《Cancer chemotherapy and pharmacology》2014,74(1):117-123
Purpose
This phase I study investigated the safety, dose-limiting toxicity, and efficacy in three cohorts all treated with the mTOR inhibitor everolimus that was delivered (1) in combination with 5-fluorouracil with leucovorin (5-FU/LV), (2) with mFOLFOX6 (5-FU/LV + oxaliplatin), and (3) with mFOLFOX6 + panitumumab in patients with refractory solid tumors.Methods
Patients were accrued using a 3-patient cohort design consisting of two sub-trials in which the maximum tolerated combination (MTC) and dose-limiting toxicity (DLT) of everolimus and 5-FU/LV was established in Sub-trial A and of everolimus in combination with mFOLFOX6 and mFOLFOX6 plus panitumumab in Sub-trial B.Results
Thirty-six patients were evaluable for toxicity, 21 on Sub-trial A and 15 on Sub-trial B. In Sub-trial A, DLT was observed in 1/6 patients enrolled on dose level 1A and 2/3 patients in level 6A. In Sub-trial B, 2/3 patients experienced DLT on level 1B and subsequent patients were enrolled on level 1B-1 without DLT. Three of six patients in cohort 2B-1 experienced grade 3 mucositis, and further study of the combination of everolimus, mFOLFOX6 and panitumumab was aborted. Among the 24 patients enrolled with refractory metastatic colorectal cancer, the median time on treatment was 2.7 months with 45 % of patients remaining on treatment with stable disease for at least 3 months.Conclusions
While a regimen of everolimus in addition to 5-FU/LV and mFOLFOX6 appears safe and tolerable, the further addition of panitumumab resulted in an unacceptable level of toxicity that cannot be recommended for further study. Further investigation is warranted to better elucidate the role which mTOR inhibitors play in patients with refractory solid tumors, with a specific focus on mCRC as a potential for the combination of this targeted and cytotoxic therapy in future studies. 相似文献9.
Tomimaru Y Eguchi H Nagano H Wada H Tomokuni A Kobayashi S Marubashi S Takeda Y Tanemura M Umeshita K Doki Y Mori M 《British journal of cancer》2010,103(10):1617-1626
Background:
We reported recently the clinical efficiency of interferon (IFN)-α/5-fluorouracil (5-FU) combination therapy in advanced hepatocellular carcinoma (HCC). However, prediction of the response to the combination therapy remains unsatisfactory. The aim of this study was to investigate the anti-tumour effects of microRNA (miR)-21 on the sensitivity of HCC cells to IFN-α/5-FU and whether miR-21 can be used as a predictor of the response to such therapy in HCC.Methods:
Changes in the sensitivity of HCC cells (PLC/PRF/5 and HepG2) to IFN-α/5-FU were examined after transfection with pre-miR-21 or anti-miR-21. The correlation between miR-21 expression level, evaluated by qRT–PCR, and response to the therapy was also investigated in clinical HCC specimens.Results:
Hepatocellular carcinoma cells transfected with pre-miR-21 were significantly resistant to IFN-α/5-FU. Annexin V assay showed that the percentage of apoptotic cells was significantly lower in cells transfected with pre-miR-21 than control cells. Transfection of anti-miR-21 rendered HCC cells sensitive to IFN-α/5-FU, and such sensitivity was weakened by transfection of siRNAs of target molecules, PETN and PDCD4. miR-21 expression in clinical HCC specimens was significantly associated with the clinical response to the IFN-α/5-FU combination therapy and survival rate.Conclusions:
The miR-21 in HCC cell lines and clinical HCC samples is a significant modulator of the anti-tumour effect of IFN-α and 5-FU. This suggests that miR-21 is a potentially suitable marker for the prediction of the clinical response to the IFN-α/5-FU combination therapy. 相似文献10.
Addition of 5-fluorouracil to doxorubicin-paclitaxel sequence increases caspase-dependent apoptosis in breast cancer cell lines 总被引:2,自引:0,他引:2 下载免费PDF全文
Zoli W Ulivi P Tesei A Fabbri F Rosetti M Maltoni R Giunchi DC Ricotti L Brigliadori G Vannini I Amadori D 《Breast cancer research : BCR》2005,7(5):R681-R689
Introduction
The aim of the study was to evaluate the activity of a combination of doxorubicin (Dox), paclitaxel (Pacl) and 5-fluorouracil (5-FU), to define the most effective schedule, and to investigate the mechanisms of action in human breast cancer cells.Methods
The study was performed on MCF-7 and BRC-230 cell lines. The cytotoxic activity was evaluated by sulphorhodamine B assay and the type of drug interaction was assessed by the median effect principle. Cell cycle perturbation and apoptosis were evaluated by flow cytometry, and apoptosis-related marker (p53, bcl-2, bax, p21), caspase and thymidylate synthase (TS) expression were assessed by western blot.Results
5-FU, used as a single agent, exerted a low cytotoxic activity in both cell lines. The Dox→Pacl sequence produced a synergistic cytocidal effect and enhanced the efficacy of subsequent exposure to 5-FU in both cell lines. Specifically, the Dox→Pacl sequence blocked cells in the G2-M phase, and the addition of 5-FU forced the cells to progress through the cell cycle or killed them. Furthermore, Dox→Pacl pretreatment produced a significant reduction in basal TS expression in both cell lines, probably favoring the increase in 5-FU activity. The sequence Dox→Pacl→48-h washout→5-FU produced a synergistic and highly schedule-dependent interaction (combination index < 1), resulting in an induction of apoptosis in both experimental models regardless of hormonal, p53, bcl-2 or bax status. Apoptosis in MCF-7 cells was induced through caspase-9 activation and anti-apoptosis-inducing factor hyperexpression. In the BRC-230 cell line, the apoptotic process was triggered only by a caspase-dependent mechanism. In particular, at the end of the three-drug treatment, caspase-8 activation triggered downstream executioner caspase-3 and, to a lesser degree, caspase-7.Conclusion
In our experimental models, characterized by different biomolecular profiles representing the different biology of human breast cancers, the schedule Dox→Pacl→48-h washout→5-FU was highly active and schedule-dependent and has recently been used to plan a phase I/II clinical protocol. 相似文献11.
Regina Gironés Sarrió Eva Calabuig Muñoz Jorge Aparicio Urtasun Pedro López Tendero Ana Yuste Izquierdo Ángel Segura Huerta 《Clinical & translational oncology》2003,5(2):88-92
Background
Oxaliplatin has been introduced to the clinical setting in combination with 5-fluorouracil/folinic acid (5-FU/FA) in an attempt to improve the response rate against colorectal cancer. It is unclear the optimum schedule of combination. In order to evaluate the response rate and toxicity profile of the combination of oxaliplatin with 5-FU/FA, according to the Mayo Clinic schedule, we evaluated our patients in a retrospective analysis.Methods
Eighteen patients with advanced colorectal cancer were treated between June 2000 and Octobor 2001. Sixty-seven percent were males, and median age was 58 years (range, 33–70). Two thirds of them had been previously treated with chemotherapy for advanced disease.Results
A total of 80 cycles have been administered, with a median of 5 per patient (range, 1–9). The response rate was 33%, and median overall survival was 16 months since the first cycle administration. Grade 3 and 4 toxic effects appeared in 33% of patients, mainly diarrhea and mucositis. Dose reductions were needed in 61%.Conclusion
Oxaliplatin combined with 5-FU/FA according to the Mayo Clinic schedule is significantly toxic. We recommend dose reduction of 5-FU in this treatment schedule. 相似文献12.
Zhen-Qian Wu Xiao-Dong Han Yu Wang Ke-Li Yuan Zhi-Ming Jin Jian-Zhong Di Jun Yan Ye Pan Pin Zhang Xin-Yu Huang Zhi-Gang Wang Qi Zheng 《Cancer chemotherapy and pharmacology》2011,68(1):87-96
Purpose
The aim of this study was to investigate the relationship between changes in IL-1?? expression and intestinal apoptosis after chemotherapy. And we further determine whether interleukin-1 receptor antagonist (IL-1Ra) reduces apoptosis in vivo after 5-fluorouracil (5-FU) chemotherapy in the small intestine.Methods
Intestinal mucositis was induced in mice by intraperitoneal injection of a single dose of 5-FU (200?mg/kg). IL-1Ra (1?mg/kg) was injected subcutaneously twice daily after 5-FU injection. 5-FU-induced intestinal apoptosis was detected by TUNEL assay. The expression of IL-1?? induced by 5-FU in local intestinal tissue was examined by RT-PCR and immunohistochemistry. Assessment of 5-FU-induced mucositis (histology, diarrhea scores, bowel weight) was performed. The apoptosis-related proteins were investigated by western blotting analysis. The proliferation of intestine was examined by immunohistological staining of PCNA. Viability of IEC-6 cells was determined using the CCK-8 assay. The apoptosis of IEC-6 cells was examined by Hoechst 33342 staining.Results
The variation of IL-1?? expression induced by 5-FU was in accordance with the changes in intestinal apoptosis. Administration of IL-1Ra could block the destructive effect of IL-1?? and reduce apoptosis in the small intestinal crypt after chemotherapy. The protection against apoptosis was in accordance with the reduction of the up-regulation of Bax and caspase 3 and the elimination of the down-regulation of Bcl-2 and Bcl-xL. Moreover, IL-1Ra attenuated the severity of intestinal mucositis induced by 5-FU and enhanced intestinal crypt proliferation. In vitro experiments showed that IL-1Ra suppressed apoptosis and increased cell viability in enterocyte IEC-6 cells treated with 5-FU. Additionally, IL-1Ra did not affect the chemotherapeutic effect of 5-FU in tumor CT-26 xenograft mice.Conclusions
Our studies elucidate that IL-1?? is quite possibly involved in and mediated the course of intestinal apoptosis after 5-FU chemotherapy. Administered with IL-1Ra protects mice against intestinal apoptosis induced by 5-FU, relieves mucosal impairment of the small intestine, and facilitates the recovery of the intestinal mucosa. IL-1Ra treatment offers a novel promising strategy for the prevention and cure of chemotherapy-induced intestinal mucositis in clinical practice. 相似文献13.
Jorgensen TJ Tian H Joseph IB Menon K Frost D 《Cancer chemotherapy and pharmacology》2007,59(6):725-732
Purpose
ABT-751 is an orally active antimitotic agent that is currently in Phase II clinical trials. This agent binds to the colchicine site on ß-tubulin and inhibits polymerization of microtubules. This disruption of microtubule dynamics leads to a block in the cell cycle at the G2/M phase, and promotes apoptosis. ABT-751, as a single agent, has antitumor activity against a series of xenograft models including non-small cell lung cancer (NSCLC) and colon cancer. The current studies were conducted to determine whether ABT-751 enhances antitumor activity of standard cytotoxic therapies currently in clinical use.Methods
Efficacy of ABT-751, in combination with cisplatin, 5-FU, and radiation, was evaluated in the Calu-6 NSCLC, HT-29 colon, and HCT-116 colon carcinoma xenograft models, respectively. Tumor-bearing athymic mice were treated with ABT-751 orally once a day at 75 or 100 mg/kg/day on a 5-days-on, 5-days-off schedule for two cycles.Results
Efficacy of ABT-751 at 100 mg/kg/day was tested in combination with cisplatin at its maximum tolerable dose (MTD) (10 mg/kg/day, i.p. x1) in Calu-6 tumor-bearing athymic mice. The percent treated/control (%T/C) tumor volume ratios on day 38 were 35, 37, and 6, and the percent tumor growth delay (%TGD) values were 71, 65, and 188 for cisplatin, ABT-751 and the combination groups, respectively. HT-29 colon tumors were used to test ABT-751 in combination with an MTD of 5-FU, 30 mg/kg/day, i.p., q.d. x5. The %T/C ratios on day 38 were 22, 28, and 5 and the %TGD values were 75, 75, and 150 for 5-FU, ABT-751, and the combination groups, respectively. Treatment of HCT-116 colon carcinoma tumors with ABT-751, concurrent with the radiation treatment, was able to both enhance radiation-induced tumor regression, and delay the time to recurrence and progression. Growth curves allowed calculation of enhancement of radiation-induced growth delay (defined as the additional time required for a treated tumor to reach four times its original size) of 2, 9, and 12 days, for ABT-751 alone, radiation alone, and the combination, respectively.Conclusion
Collectively, these studies demonstrate that ABT-751 enhanced efficacy of standard cytotoxic therapies in a variety of tumor xenograft models, and that enhancement was at least additive in all systems. 相似文献14.
Catalano V Vincenzi B Giordani P Graziano F Santini D Baldelli AM Alessandroni P Schiavon G Rossi D Casadei V D'Emidio S Luzi Fedeli S Tonini G Fiorentini G 《Gastric cancer》2012,15(4):419-426
Background
The combination of docetaxel, cisplatin, and 5-fluorouracil (5-FU) has demonstrated a survival advantage over cisplatin and 5-FU, but with substantial hematological toxicity. We aimed to evaluate the efficacy and toxicity of a sequential regimen with cisplatin, leucovorin, and 5-FU (PLF) followed by docetaxel in metastatic gastric cancer patients.Methods
Treatment consisted of 4 cycles of biweekly PLF (cisplatin 50?mg/m2 as a 30-min infusion on day 1, leucovorin 200?mg/m2 in a 2-h infusion, and 5-FU 2,800?mg/m2 in a 48-h continuous infusion starting on day 1) followed, in cases of response or stable disease, by 3 cycles of docetaxel (75?mg/m2, every 3?weeks).Results
Thirty-four patients were enrolled, with an average age of 64?years (range 34–69). The main cumulative grade 3–4 toxicities were: neutropenia (38.2%), febrile neutropenia (11.8%), and fatigue (14.7%). After the planned 7 cycles of treatment, the overall response rate was 38.2% (95% confidence interval [CI] 21.9–54.6), with 3 complete and 10 partial responses. Median progression-free survival and overall survival were 4.8 and 10.6?months, respectively.Conclusions
For patients with metastatic gastric cancer, the sequential administration of cisplatin, leucovorin, 5-FU, and docetaxel may be an effective palliative option and offers a far more favorable toxicity profile than the simultaneous use of docetaxel, cisplatin, and 5-FU. 相似文献15.
Objective
The aim of the study was to observe the transfection efficacy of hepatitis B virus envelope (HBVE) and evaluate its ability as a gene transfer vector for liver cancer cells.Methods
To obtain HBVE, the supernatant fluid of HepG 2.2.15 cells was mixed with a PEG8000 solution for concentration and was inactivated by β-propiolactone. The acquired HBVE was used to pack pIRES2-EGFP to test its package ability. Then, we examined its quantity and quality with ELISA, PCR, SDS-PAGE and electron microscopy. The pIRES2-EGFP was packed with HBVE and obtained the product HBVE-GFP. The pIRES2-EGFP was packed with liposome and obtained the product liposome-GFP. HBVE-GFP and liposome-GFP were used to transfer HepG 2 cells to study the transfection efficiency. HBVE-GFP was used to transfer HepG 2, A549, HeLa and FB cells to study the targeting ability. The green fluorescent protein (GFP) expression was observed under a fluorescent microscope. The rate of GFP positive cells was determined by flow cytometry.Results
1. The acquired HBVE could retain the surface protein HBsAg + pre S1 + pre S2 and had no virus DNA. It had good package ability for pIRES2-EGFP. 2. Transfection efficiency: The GFP could be observed in both the liposome group and HBVE group under the fluorescent microscope. But the HBVE group had a higher fluorescent intensity than liposome group. The transfection rate of liposome group was 49.97% ± 2.37% while the HBVE group was 70.65% ± 3.15% and the fluorescent intensity of the HBVE group was 3–4 times (P = 0.000) for liposome group with the determination of flow cytometry. 3. Targeting ability: The GFP could be observed in the four groups under the fluorescent microscope. The HepG 2 group had the highest fluorescent intensity among the four groups. The transfection rate of HepG 2 group was 71.35% ± 0.03% which was highly expressed than other groups (P = 0.000) and the fluorescent intensity of the HepG 2 group was 2–3 times (P = 0.000) for the other 3 groups with the determination of flow cytometry.Conclusion
HBVE can be constructed successfully with the methods of PEG8000 and β-propiolactone from the supernatant fluid of HepG 2.2.15 cells. The HBVE can be a candidate gene transfer vector for liver cancer cells. 相似文献16.
Purpose
To determine the maximum-tolerated dose (MTD) of a 24-h continuous infusion of 5-fluorouracil (5-FU) when administered in combination with a fixed weekly dose of docetaxel and cisplatin in patients with advanced gastric cancer.Methods
Patients with advanced gastric adenocarcinoma (n = 21) received a weekly regimen of docetaxel, cisplatin and 5-FU (DCF) for 3 consecutive weeks every 4 weeks. The doses of docetaxel and cisplatin were fixed at 33.3 and 30 mg/m2, respectively. The dose of 5-FU was increased from a starting dose of 1,000 mg/m2 to the MTD.Results
A total of 53 cycles of chemotherapy were administered (median = 3 cycles/patient). The MTD of 5-FU was 1,750 mg/m2. All 21 patients were assessed for toxicity and 19 patients (90%) were evaluated for response. Both grade 3–4 hematologic and non-hematologic toxicities occurred in less than 10% of patients and there were no treatment-related deaths. Among the 19 patients, we observed 1 complete and 4 partial responses for an overall response rate of 26% (95% CI: 6–46%). This rate increased to 39% (95% CI: 12–66%) in 13 chemotherapy-naïve patients.Conclusions
A consecutive weekly DCF regimen at 4-week intervals appears feasible for advanced gastric cancer with a favorable toxicity profile. The recommended doses are 33.3 mg/m2 of docetaxel, 30 mg/m2 of cisplatin and 1,500 mg/m2 of a 24-h continuous intravenous infusion of 5-FU. The response of this weekly regimen in our study was favorable and deserved further investigation in a phase II trial. 相似文献17.
Rong Mu Qi Qi Hongyan Gu Jia Wang Yong Yang Jingjing Rong Wei Liu Na Lu Qidong You Qinglong Guo 《Molecular carcinogenesis》2009,48(12):1159-1169
Oroxylin A, a naturally occurring monoflavonoid extracted from Scutellariae radix, exhibits anticancer activity and induces apoptosis in human hepatocellular carcinoma HepG2 cells according to our previous data. In this study, we investigate whether p53 is involved in oroxylin A‐triggered viability inhibition and apoptosis induction in cancer cells. In a panel of different cancer cell lines, more potent inhibitory effects of oroxylin A were observed in wtp53 cells than those in mtp53 or p53‐null cells. Moreover, p53‐siRNA‐transfected HepG2 cells showed lower levels of apoptosis induced by oroxylin A than control‐siRNA‐transfected cells. Likewise, after oroxylin A treatment, p53‐null K‐562 cells displayed promoted apoptosis rate when transfected with wtp53 plasmid. Western blot and real‐time RT‐PCR assay revealed that oroxylin A markedly upregulated p53 protein expression in HepG2 and p53‐overexpressing K‐562 cells, but had no influence on p53 mRNA synthesis. Furthermore, after co‐treatment with cycloheximide, oroxylin A still exerted a little effect on p53 expression. The negative regulator of p53, MDM2 protein was detected, and downregulated expression was observed. In the presence of MG132, an inhibitor of proteasome‐mediated proteolysis, no change in p53 expression was obtained. Additionally, the antioxidant N‐acetyl‐L‐cysteine could obviously abrogate p53 stabilization triggered by oroxylin A. Therefore, it is summarized that oroxylin A stabilized p53 expression and induced apoptosis at the posttranslational level via downregulating MDM2 expression and interfering MDM2‐modulated proteasome‐related p53 degradation. This indicated that oroxylin A could be served as a potential, novel agent candidate for cancer therapy. © 2009 Wiley‐Liss, Inc. 相似文献
18.
Junichi Kurebayashi Mamoru Nukatsuka Hiroshi Sonoo Junji Uchida Mamoru Kiniwa 《Cancer chemotherapy and pharmacology》2010,65(2):219-225
Purpose
Our previous study indicated that concurrent administration of 4-OH-tamoxifen (TAM) and 5-fluorouracil (5-FU), but not doxorubicin (Dox), resulted in additive antitumor effects on endocrine-responsive breast cancer cells. We further clarified the effects of combined administration of endocrine therapy with chemotherapeutic agents in this study.Methods
Concurrent treatment with 4-OH-TAM and paclitaxel (Ptx) was investigated in estrogen receptor (ER)-positive breast cancer cells. Additionally, the combined effects of estrogen depletion from culture medium mimicking estrogen ablative therapy with 5-FU, Dox, and Ptx were investigated.Results
Concurrent treatment with 4-OH-TAM and Ptx yielded less than additive antitumor effects in ER-positive breast cancer cells, as observed with Dox in our previous study. More interestingly, estrogen depletion with 5-FU, but with neither Dox nor Ptx, yielded additive antitumor effects on these cells. We also performed preliminary experiments to elucidate the mechanisms of action responsible for the combined antitumor effects observed. Ptx up-regulated the level of expression of one of the molecules related to TAM resistance, Eph-A2, as observed with Dox in our previous study. Estrogen depletion down-regulated the level of expression of one of the molecules related to 5-FU resistance, thymidylate synthase, as observed with 4-OH-TAM in our previous study.Conclusions
These findings, together with those of our previous study, suggest that concurrent treatment with endocrine therapy, administration of TAM, or estrogen ablative therapy and 5-FU but neither Dox nor Ptx may yield additive antitumor effects on endocrine-responsive breast cancer. 相似文献19.
Fotios Loupakis Gianluca Masi Lorenzo Fornaro Enrico Vasile Giacomo Allegrini Eloise Fontana Cristina Granetto Lisa Salvatore Lucia Mentuccia Michele Andreuccetti Enrico Cortesi Marco Merlano Stefano Cascinu Alfredo Falcone 《Cancer chemotherapy and pharmacology》2010,66(3):559-566
Purpose
5-Fluorouracil (5-FU) plus cisplatin (C) can be considered a standard option for advanced gastric cancer (AGC). Irinotecan (Ir) and docetaxel (D) are active agents with no complete cross-resistance with C and 5-FU. Concomitant combination of Ir or D with C and 5-FU is feasible, but with substantial toxicities. A different way to include all active agents in first-line treatment of AGC may be to use them sequentially. We aimed to evaluate the activity and the safety profile of sequential chemotherapy with 5-FU-based doublets with C, Ir and D in the first-line treatment of AGC.Methods
We conducted a phase II study of first-line sequential chemotherapy in metastatic GC. Treatment consisted of 3 cycles of C + infused 5-FU and leucovorin (CFL) followed by 3 cycles of Ir + 5-FU/LV (IrFL) followed by 3 cycles of D + 5-FU/LV (DFL). Primary end-point was response rate.Results
Forty-six patients were enrolled, median age 60 years, sites of disease (single/multiple) = 9/37, PS 0/1 = 27/19, gastric/gastro-oesophageal junction = 39/7. Median number of cycles was 9. Main grade 3–4 toxicities were neutropenia (37%), febrile neutropenia (2%), diarrhoea (4%), stomatitis (9%). Response rate after the planned 9 cycles was 45% (15 partial and 5 complete responses among 43 evaluable patients). Median PFS and OS: 6.8 and 11.1 months, respectively.Conclusion
This sequential treatment is feasible with a favourable safety profile and produced encouraging results in terms of activity and efficacy. 相似文献20.
Chunxiao Ji Fenglian Ren Heng Ma Ming Xu 《Journal of experimental & clinical cancer research : CR》2010,29(1):50